Estrogenic substances



Patented Dec. 7, 1948 UNITED STATES PATENT OFFICE ESTROGENIC SUBSTANCES Ralph C. Tallman, Morristown, N. J., and Alfred H. Stuart, New York,

N. Y., assig'nors to Schieffelin & 00., New York, N. Y., a corporation of New York No Drawing. Original application May 30, 1944,

Serial No. 538,089. Divided and this application November 10, 1945, Serial No. 627,972

4 Claims. (Cl. 260613) about the physiological changes known as estrus.

or heat periods in female animals, or the follicular phase of the menstrual cycle in human females. Ordinarily such substances are secreted estrogenic and bactericidal properties are possessed by compounds having the structure in which each X is H, alkyl, acyl of aliphatic or aromatic type, or an inorganic ester radical such as SOsH or POsHa Which may be obtained by condensing one of these compounds having OH terminal groups with an inorganic acid; and R is H oralkyl, at least one R being alkyl; in which the OXgroups may be symmetrical or not, and

. [may be the same or different; and in which each by the ovaries and the physiological changes brought about by the normal functioning of these ovarian secretions in conjunction with other bodily functions.

However, due to disease, illness, surgical intervention or many other causes, the normal functioning of the ovaries, and the consequent secretion of estrogenic substances, may be ab l sent or impaired. This condition may, in turn; give rise to other types of physical and mental illnesses. In such instances it often becomes advisable or necessary to administer therapeutically, for example, by injection or by feeding; estrogenic substances produced outside the body of the patient to substitute for the absent or diminished natural secretions.

For industrial elaboration, estrogenic subalkyl B. maybe the same or different.

The invention is further based on the further discovery that" compounds having the following type formulae are especially and uniquely bene- 'ficlal, and it is a further object of the invention stances may be obtained from natural sources,

such as the excretions of pregnant female mammals. For example, the urine of pregnant female horses may be collected and subjected to various processes designed to concentrate and purify the estrogenic substances contained therein, and thus to isolate them in a condition suitable for therapeutic administration in the manners and for the purposes named above. Such procedures are devious, time-consuming, and expensive.

This invention describes artificial estrogenic substances which may be prepared from simple chemical compounds. When the products described in this invention are employed, no recourse to estrogenic substances from natural sources is necessary. The compounds described below will induce physiological changes like those brought about by estrogenic substances from natural sources as outlined above. These compounds may be produced simply and inexpensively in commercial quantities, and may be used therapeutically for treatment of conditions arising from absence or diminution of the bodily produced estrogenic substances.

This invention is based on the discovery that to utilize said compounds as estrogenic and bactericidal compoundsj" Type I x0 H H a ox I I rec H H H I in which X is H, alkyl, or acyl, and R is alkyl.

' a Type II -xo" "H; R H OX.

l H H in which X is H, alkyl, or acyl, and R is alkyl.

Type III x0 1 1 Ill. 1 ox t H l in which X is H, alkylyor acyl, and each R is alkyl. l.

Type IV Type V x0 I R R R n i1 is it in which X is H, alkyl, or acyl, and each R is alkyl.

The OX radical may be in the ortho, meta, or

. 2,455,535 3 4 para positionineach of the foregoing types, and tion oi-crystals ,or by failure of the residue to need notbe symmetrically positioned; "j boil-at a constant temperature, the same process Examples of the production of compounds of the may be repeated until reduction is complete. above types are as follows: The final product of this step, 1,3-di (p-methoxyphenyl) -pentane may be purified by distillation,

EXAMPLE 1' PRODUCTION OF TYPE "and is a'colorless liquid which boils at l60-165 o. Specific m m of the series illu trated bx ,under 1 mm. pressure. It may be converted into yp I ay be p pa ed in the renewing man'neri {thecorrespondingphenolic product as follows: 4 r m f pm oxy phenone and as sm 2.0 grains of the 1,'3-di (p-methoxyphenyD- of anisaldehyde are dissloved in 150 cc. of alcohol. 10 pentane are hydrolyzed by dissolving in 6 cc. The solution is stirred vi r u ly, and 150 00, o glacial acetic acid, to which solution cc. of 57% 1 aqu us d um hyd xide solution.isgradilQ-Rediiepus .hydriodic acid is added. The reaction y added in Small p t o heP QP@ mixture is njiaintained under reflux at the boilrates slowly from the solution and becomes 'ing"iaoiii,t for 15 minutes, then 4 cc. of glacial C ys ne 0 t ad t o of s "S r n '15: aceti'c' acid and 5 cc. of the hydriodic acid soluis continued for two hours after the addition tion are added, and refluxing continued for a of sodium hydroxide; is complete, and the total of four hours. The mixture is poured into mixturefls then ,allowed to st,and1 2 to, 24 water, thesolution made alkaline with excess hours at 0 C. The p,p'- dimethoxy chalcone potassium hydroxide, and filtered with the aid thus p c (888 t p I below) is removed ofcharcoal. The phenolic product thus obtained by filtration, washed with ice-cold alcohol 7 (see Step IV below) is precipitated by acidification and water, and may be purified by crystallizaof the filtrate, extracted with ether, and, after the tion:from about 400 cc. of alcohol from ,which evaporation of the ether. distilled slowly at. 150 it separates in bright yellow. crystals'QM. .P. C; under high vacuum. The distillate is a color- 100-101" C. a 25 less, glass-like product which solidifies on long The p,p-dim ethoxy chalcone is reacteddsee standing. This compound is 1,3-di-(p-hydro- Step II below) with ethyl magnesium bromideas xyphenyl pentane, where R is the ethyl radical.

L on on; anger cmQ-QE-QmEH-Q-wm omoOg-om-znOocm reacted cuiwo-om cm-icn-gocm t i t Step IV I oH,o-C -oHi-.CH=OH'C -ocH3- (hydrolysis) Ho-omoHi-oHC -on follows: Asolution of 31 grams of ethyl magnesium Any product corresponding to Type I can be bromide in 450 cc. dry ether is. maintained at produced by following the basic outline of the 10' C; and vigorously stirred while 20 grams of process andequations set forth herein above, using the chalcone is added insinall quantities. The an alkylmagnesium halide having the desired cooling bath is then removed, and stirring connumber of-carbonatoms in its alkyl group. The tinued fortwo and one-half hours at room temcondensation can also be carried out in acid meperature. The reaction-mixture is-"poured into diuin', using-a mineral acid as the condensing 1200 cc. ice water containing 150 cc. hydrochloric agent acid, after which the ether layer is separated and the aqueous layer extracted once with ether. 2..PRODUCTION OF TYPE II The ether is evaporated from the combined 'solu-' tions and the product which remains is purified ifi members of the Series illustrated by by distillation under high vacuum and crystal- 4-; m be Prepared in the following lization from alcohol. Thewhite crystals of the W grams of anisaldehyde and 22 grams of product, 1,3-di (p-methoxyphenyl)-pentanone-1 m exv utv a thoroughly mixed (Where R is the ethyl group) have a melting point a d e m o d hydrogen chloride gas bubbled of 70C. ,This compound may be converted-into mtOI h? mixture until the total Weight is 1,3-di (p-methoxyphenyl)-pentane as follows; 5 lf fi b g s The reaction mixture, 9 grams of the pentanone are mixed with so WhlPh p o es e y d k ed, is shaken grams of amalgamated zinc, 45 cc. water, 120 cc. n i 1t becomes pasty, due to the separation o hydrochloric acid, 35 cc. of toluene, and 2 co. t P d t, a d is then allowed to stand for acetic acid, and the reactionmixture heated under fifteen; hours. The entire mixture is dissolved reflux at the boiling point for twenty-eight hours in b nzene nd the benzene solution extracted e Step III b l w), It isthe med e with water, with sodium carbonate solution and tracted with ether, the ether layer separated,.and again with water. The benzene is then evapall solvents removed therefrom by evaporation. grated. and the residue maintained at 150 C. until If reduction is not complete, as shown by separaevolution of hydrogen chloride has ceased, after which it is subjected to distillation under 'rewithzethyl magnesium bromide in the following duced pressure. After a small amount of lower manner: A solution of 8 grams of the chalcone boiling forerun, which is discarded, the desired in 150 cc. of dry ether is added slowly to a vigorproduct distills at 190-200 C. under 1 mm. presously stirred-sol ion f 13-2g1amS f yl ma sure. The product, 4,4'-dimethoxy-a-ethyl chalnesium bromide in 85 cc. of dry ether maintained cone, where R. is the ethyl group, (see Step I at a temperature of l0?' C. Stirring is conbelow) is a bright yellow oil. tinued for :three hours at room temperature after '10 grams of the 4,4'-dimethoxy-u-ethyl chalwhich the reaction mixture is poured into 500 cc. cone from the previous procedure is dissolved in of ice water containing 750 Of hydrochloric acid- 50 cc. of absolute alcohol, 1 gram of a copper- The etherv layer is separated, the aqueous soluohromium oxide catalyst added, and the mixture tion extracted once with ether and the ether submitted to high-pressure hydrogenation at 220 solutions combined. After evaporation of the and about 150 atmospheres pressure for 5 hours ether the residue is distilled under high vacuum. in an appropriate machine. After cooling, the The distillate, 1,3 P- yD y y hydrogen pressure is released and the solution repentanone-l, where. R and. R1 are ethyl radicals, moved from the hydrogenation apparatus and filis a pale yellow oil (See p H W This tered free of the catalyst. On cooling thefiltrate, may be further converted as follows: the product, 1,3-di-(p-methoxyphenyl) -2-ethyl- 10 grams ofthe ethylpentanone as prepared in propane, where R is the ethyl group crystallizes Step II-is dissolved in 50 cc. of absolute alcohol, as a white solid which may be filtered off. It 1 gram of a copper-chromium oxide catalyst has a melting point of 43. By this method of added, and the mixture submitted to high pressure hydrogenation, both the double bond and the hydrogenation at 220 and about 150 atmospheres ketone group in the starting material are compressure for 5 hours in an appropriate machine. pletely reduced (see Step II below). If desired, After cooling, the hydrogen pressure is released the product from this hydrogenation may be and the solution removed from the hydrogenaconverted into the corresponding phenolic prodtion apparatus and filtered free of the catalyst. uct as in Example I (see Step III below). The alcohol is removed from the filtrate by evap- Pnonucrron or TYPE II Step I Et Step II CH|0-C -E-E=CHO-OCHi+hydrogenation ommO-cm-E 11-0300 on,

Step :11

CH;OOCHa-EHCH1OOCH3 (hydrolysis) noOcm-on-om-O-on t Er Any compound corresponding to the formula of Type 11 may be produced by following the basic outline of the process set forth above, takoration and the product (see Step III below), which is l,3-di(p-methoxyphenyl)-2-ethylpentane, where R and R1 are ethyl radicals is dis-:

I 8 ing care in Step I to select the proper ketone for tilled at 170 175 C. ier 1 ress 6' It combination with the aldehyde.

IS. a colorless liquid and may be converted into EXAMPLE 3' PRODUCTION OF TYPEIII the corresponding phenolic compound as in Specific. members of the series illustrated by Example I (see Step IV below).

PRODUCTION OF TYI'E III I Step I g j I I l 0 er: I

' Step II i Step III cmoO-o-on-pnO-oom (reduction) cmoOoH'r cH- 431100011:

, t it is i it,

Step IV 1k 1 n I v R Bl Type III may be prepared in the following man- R and R1 may be the same or different alkyl her: The first step in this preparation is identical radicals. In general any desired compound corwith the first step of Example 2, for the production responding to this type formula may be made by of 4,4'-dimethoxy-a-ethyl chalcone (see Step I using. Step}, a ketone having the proper below) V alkylradical and, in 'Step II a magnesium bromide The chalcone as produced above may be reacted compound having the properallsyl radical.

l Elin'c'e the' carbon atomsto which the alkyl distillation water.lisilevolvedriand the resulting radicals are'attaohed are asymmetric in this type product- I is; 3,5'-di(p=methoxyphenyll eheptene-Zi; ofcompou'nd "the product produced may be a where Rand. R1 are'iethylradicalsazceesteprilll single racemate ora mi'xture of racemates and below). This is then treated. accordin'g to'step; the individual racemates of-such'mixture may be IV as follows: 512, 3 l l T separated'byany suitable inethod, a preferred 4 grams of the3;5-di'tp-methoxyphenyl) -hepl-- methodbeing disclosedin our copending applitene-Z is dissolved in 70 cc; of glacial acetlcvacld cation Serial No."538,090 filed: May 30,1944, now and 0.0.4 gram of platinum oxide catalyst/added. U; S. Patent 2,400,034.. i For example, when R. and The container is'then attached; to; a machinejfcr R1 'are ethyl 'groupasthe'intermediate compound 10 catalytic hydrogenation; the hydrogen applied-i; pmducedi;as';shown.'in Step II is in the form of andthe, mixture shaken untilione-moleculan'equive, two racemi'c' mixtures; one liquid and one' solid. ale'nt of hydrogen has beenconsum'edw Theimixs: Thesermixtur'es may be separated by dissolving ture is then decanted fromlthewcatalyst, 'dflutcd: them; in a solvehtsuchas alcohol and crystallizing with water, neutralized with N aOILcandtthe prod: thesolid-racemic mixture fromthe solution. By 5 uct extracted withretherg-The, 'ether zisr-eyopoe; evaporating the. solvent fromithe mother liquid, rated at room temperature, andnthe'iresidue'dism the liquid racemic mixture may be recovered. tilled. under reduced. pressurelvithei product thus: Either the solid or the'liquid-racemic mixture may obtained (see Step IV; below) ,is a colorleisi oily: then besubjected to the reactions shown in Steps liquid and is- 3,5,-di(p methoxyphenyhrheptane; III and IV. As alsoestatedin that application, where;R.and;R.1 are;ethyli radicals andnnay, be; an individual .racemic mixture of two stereoconverted intox'thea corresponding; phenolic com-F isomeric forms of thistypeof compound may pound as in Exampleil (-seeStep .V'belowlm T PRODUCTION or'T's'zPa IV i I I Step v.14 GEOGGH-CHPCHOOCH: HO

have greater estrogenic' potency than thatof the conglomerate of"s'tereoi s'omers. v

EXAMPLE 4.PRODUCTION OF TYPE IV 5O Specific members of the series illustrated in Type IV may be prepared in the following manner: p,p-dimeth'oxychalcone is prepared in exactly the manner described in "Example I (See Step I below). This is then treated as follows:

Following exactly the same directions as de-y. scribed in Example 1, Step II, the p,p'-dimethoxy chalcone is converted into 1,3-di(p-methoxy- I, I t phenyl) -pentanone-1. (See Step 11 below.) EXAMPLE 5' PR0DUCTION 'V This is then treated according to Step III as Q Specific members of the series illustrated by follows: Type V may be prepared in the following man- A solution of 10 grams of the pr'itanone in 130 v ner: The first two'steps in this process are identiccfdry ether may be added'slowlywith vigorous ea] in all respects with the firstl two steps'i n 'lil xstirring to a solution of 8.9 grams of ethyl mag: ample 3 for the production of 1,3-di(p-methoxynesium bromide in 60 cc. dry ether. After the] phenyD-2-ethyl pentanone-l (see Steps I and II addition-of the pentanone has been completed, below). This may be converted into other prodthe mixture is warmed on a steam bath for five ucts as follows: I I hoursfafter which the mixture'is poured into a 8.0 grams of the ethyl pentanon obtained in mixtur 0170 ccice W r. and 100 cc.- hy SteplI are dissolvedindry ether and added slowly hlor la 'idfi e th rla'y r is, pa d; a tdasoluti on off ethyl magnesium bromide me. the ether removed. The residue. is subjected t0 pared from 5.0' grams of ethyl bromide and l.2 vacuum distillation, n obtained as a color rams or magnesiumturiungs lii'aiihydrous ether." less oil which hasia boiling point of 183-18? C. when the adaiticiro'r the peritanor'i'has' b at2m yiiidwhichsolidines' to aisoli'd compound completed, the reaction mixture is warmed meltingaft'erpurlficationat s'r'c; During this asteamtath iornvencurs eft'er'wiubfi it is I!!! w 4 "it 2 R n R1 maybe. e ew di fe en al radicals. Ingeneral, any compoundconforming to this type formula may be made byu'si'ng'in Steps lIgand III magnesium bromide compounds 2 having alkyl radicals of the constitution desired in the final product.

Since the carbonatoms to whichtfialkyl radicals are attached are asymmetric in this typeo: compound, the product may be a single racemate .or a mixture of racemates and the individual racemates of such mixture may be separated.

9. 10 poured into a mixture of 700 cc. ice water and 100 mide was used in each of the foregoing reactions cc. hydrochloric acid. The ether layer is sepaand excellent results are obtained by its use,'but rated, dried, and the ether removed. The residue it can be replaced by any alkyl magnesium halide is subjected to vacuum distillation, and is obexcept the fluoride.

tained as a colorless oil., During this distillation, The compounds ofthis invention are preferably water is evolved, and the resulting unsaturated administered by intramuscular injection and show product is 4-ethy1- 3,5 di(p methoxyphenyl) the reaction of the ovarian follicular hormone.

heptene-Z, Where R1 and R2 are ethyl groups. In the present specification and claims the sym- See Step III below. I I bol The 4-ethyl-3,5-di(p methoxyphenyl) heptene-2 from the previous step is dissolved inTIO cc. glacial acetic acidand subjected to catalytic hydrogenation as described in Example 4, Step IV, until no more hydrogen is consumed The mixture is then decanted from the catalyst,-dilsignifies the benzene nucleus.

The dihydroxy compounds of this invention have the general formulauted with water, neutralized with sodium hy- H0 R R 0 droxide, and the product extracted with-ether The ether is evaporated at room temperature, i l k v a and the remaining liquid distilled under reduced pressure. The product thus obtained (see Step '20 where R is selected from the group consisting of IV below) is a colorless oily liquid and is 4-ethylhydrogen and alkyl radicals, at least one of said ,5-di(p-m yD p e, Where R, R1 R substituents being an alkyl radical. The hyand R2 are ethyl d c and ay be converted droxy substituents may be in the ortho, meta, or into the corresponding phenolic compound, as in para-position, and symmetrical or unsymmetrical. Example 1. g The invention also includes generically the'ether PRODUCTION or TYPE V I v I a Step I oH.oo=o omo-Qg cmm omoOcfiAaqmQ-oom Step II cmol -o=on oom +.'R:MgBr omoQe-bm-cn-Qoolh 0 R1 w g l t l t: Step III r onloOr -on on-o oom RMgBr crime-Georgi:- 011000113 0 R1 R1 1 g R; it, 5 7 Step IV Gino-Oo- H- oil-O0 CH5 hydrogenation cmoOoH- 03- 0110-0 om 6R1 R7 I I l t: Step v CHaO-OoH-J JH-CHOOCE HQ-QoH-,-c :H--GH C -OH R R1 1kg R R1 1L1: R, R1 and R2 may be the same or different alkyl and ester derivatives of these hydroxy compounds.

radicals. In general, any compound correspond- Either or both of the hydroxy substituents may ing to this type formula may be made by employexist in the form of their functional derivatives, ing in Step I a ketone having the desired alkyl that is, ether and ester derivatives, and those corradical, and in Steps II and III by employing 5 responding ether and ester compounds may also magnesium compounds having the desired alkyl be symmetrical or unsymmetrical. radicals. Mixtures of the racemates produced Further support for this generic statement, in

may be s p a d t th indiv dual ra mat s. addition to that already set forth, is r videdby e. g. by the method disclosed in the copending the following:

application hereinabove referred to. .60 Example 1 shows t production of In the above reactions the terminal group was H C methoxy, but it may be any alkoxy group, and ll g 5 may be obtained in the final product, by the use O T 0 of appropriate starting compounds in Step I or H by converting the OH groups in the final phenolic By substituting meta-methoxyacetophenone for compqundwhen a terminal! acyl group is the para compound in Example 1 in column 3 sired m the final compound It may be iconven" and proceeding exactly as prescribed in that exiently obtained by converting the OH groups in ammethere is obtained the final phenolic compound into RCOO groups. (A)

The terminal groups may be in the ortho, meta or para position, symmetrical or not. To produce u a I O terminal groups which are esters of inorganic acids, the phenolicterminal group is condensed v a I with an appropriate inorganic acid, such as phos- "By substituting orthometho'xy-acetophenone phoric and sulfonic acid. Ethyl magnesium bro- .75 for the para compound in Example'l and proceeding otherwise exactly as in that example, there is Obtained B t H: H: CzHi v l. s. Q A Q substituting orthm'methoxybeiisaldehyde for the para compound in Example 1 and n-propyl magnesium bromide for ethyl magnesium bromide and proceeding otherwise exactly as in that example, there is obtained Example 3 shows the production of i H: 01H: GzHt By substituting orthu methoxybenzaldehyde for the para compound in Example 8 and otherwise proceeding exactly as in that example, there is obtained 0H CzHs G:Hs-' 1 l g l H0 n;

Example 4 shows the production of I i ii'fi bail v By substituting oithmmethoxybenblllehyde for the para compound and proceeding otherwise exactly as shown in that example, there is ob-.

tained Example 5 shows the production of east cat a l 0 I By substituting ortho-methoxybenzsidehyde for the para compoundaml-methyl'inagnesiu n iodide for ethyl magnesium bromide in Step III bi that example and otherwise proceeding exactly as shown in Eiiample 5, there obtained C H; Q :H CaHs The above identified compounds (in to (F) inclusive havebeen tested by subcutaneously in jecting oil solutions thereof into castrated ice male rats and said compounds have been found to possess estrogenic activity comparable to compounds shown in Examples l to 5 differing from compounds (A) to (F inclusive only in the position of the OH groups. v p

By substituting in Example 4 the orthomemoxy substituted compounds off th phi! substituted 1110*.

12 seeding exactly as in said example, there is ob tsined tam This compound possesses estrogenic activity of the same order of magnitude as the corresponding (ii-para com ound. I l a In so for as the esters are concerned, they may be obtained, in general, by esterifying one or both of the hydroity groups in accordance with the esterificatlon technique known to organic chemists; and the invention includes generically the ester derivatives of organic acids. Support for this genetic statement will be found in the following illustrative species of ester derivatives:

. 1'1! 16:1 H GtHtGO -C- C OOaHs H: II C H: H dllfin 00-04 i- 0-0 0 0 Cum:

ouiqc 00:0

I GHHuQOQOCL- J- -E-O-ooocm ts. its,

HiHiH l B: 2 wzoooQ EEC-000cm;

1 11 H omoooQ-t- 00-00 0cm IHT boiling oi! the other, the residue is crystal 13 lized from alcohol. The dibenzoate is a white crystalline solid melting at 65 C.

One gram of 1,3-di-(p-hydroxy phenyl) -2- ethyl pentane is refluxed for four hours with a mixture of 10 cc. of acetic anhydride and 0.5 gram of fused sodium acetate. After dilution with water, the mixture is made alkaline with potassium hydroxide, and extracted with ether. The ether solution is separated, the ether boiled off and the residue distilled under high vacuum. It is a thick, pale yellow oil.

Three grams of palmityl chloride is added dropwise to a solution of 1 gram of 2,4-di-(p-hydroxy phenyl)-S-ethyl-hexane in 10 cc. of pyridine. After standing overnight, the reaction mixture is worked up in the usual manner. The dipalmitate, after crystallization from alcohol, is a white crystalline solid melting at 36-38 C. All of the above esters have estrogenic properties.

As for the ether derivatives, the invention includes generically the monoor di-alkyl ether derivatives of the hydroxy compounds. Support for this generic statement is found in the foregoing description, in which it is pointed out that instead of employing in Step I methoxy compounds, alkoxy compounds in general may be substituted, and that these alkoxy groups may be in the ortho, meta, or para position in relation to the other substituents, thus producing as a final step prior to hydrolysis, alkoxy or ether derivatives in general, symmetrical and unsymmetrical. Instead of producing alkoxy or ether derivatives by starting with appropriate alkoxy compounds, it is entirely possible to convert the final dihydroxy derivatives into their corresponding ethers by known etherification methods. Various illustrative specific examples of ether derivatives are shown; as follows:

O C4Hn l 02115 511110 0051111 i H] H H, I

Ga -O As previously pointed out, there is an R substituent at one or more of the three carbon atoms of the propane bridge connecting the benzene radicals, and that R substituent is an alkyl radical in general, and those R substituents are the same or different alkyl radicals in general. Further support for these generic statements will be found in the following specific examples:

It is preferred that the number of carbon atoms in each of the alkyl substituents on the propane bridge be not greater than five, although the activity of such compounds having longer substituent chains has been proved by many experiments, numerous examples of which are found herein.

We claim:

1. Alpha, gamma-di(alkoxyphenyl) propanes in which all of the propane carbon atoms are substituted by alkyl groups of less than six carbon atoms, and in which the alkoxy groups have less than six carbon atoms.

2. 3-ethyl-2,4-di(p-alkoxyphenyl) hexane having less than six carbon atoms in the alkoxy groups.

3. A racemic mixture of two stereoisomeric forms of the substance 3-ethyl-2,4-di(p-alkoxyphenyl) hexane in which the alkoxy groups have less than six carbon atoms, said mixture having an estrogenic potency higher than the conglomerate of the eight possible stereoisomers of this substance.

4. 3-ethyl-2,4-di(p-methoxyphenyl) hexane.

RALPH C. TALLMAN. ALFRED H. STUART.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,317,607 Harvey Apr. 27, 1943 2,400,033 Tallman et al. May 7, 1946 OTHER REFERENCES Richardson et al.: Journal American Chemical Society, vol. 62, (1940), pages 413-415.

Certificate of Correction Patent No. 2,455,535. December 7,1948.

RALPH C. TALLMAN ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Columns 5 and 6, Production of Type III, Step I, for that portion of the formula c 0 columns 9 and 10, Production of Type V, Step III, right-hand portion of the formula, for

read

"-C--CH--CH" c--cg..-cg. read O 1 RI 1 R1 "Step IV, for

"-C- -CH- -CH" d --c-.cn-..cg

| L 1'68. 0 R1 1 R R1 1 column 11, lines 44 to 48 inclusive, for

(I-JIHI CIHI" CIHI 1 i C- -C-- --C-- are read A the and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 5th day of April, A. D. 1949.

[amen] THOMAS F. MURPHY,

Assistant G'ommz'ssz'oner of Patents. 

